Sidekick proteins in HIV-associated nephropathy

HIV 相关肾病中的 Sidekick 蛋白

• 批准号: 7252596
• 负责人: Lewis Kaufman
• 金额: $ 12.87万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7252596
• 关键词: AIDS-Associated Nephropathy; Actins; Address; Adhesions; Affect; Architecture; Axon; Binding; Biopsy; Bundling; Cell Adhesion Molecules; Cells; Cessation of life; Chromosome Pairing; Cultured Cells; Cytoskeleton; Data; Development; Disease; Disruption; Employee Strikes; Focal Segmental Glomerulosclerosis; Foot Process; Functional disorder; Genes; Genetic; HIV-1; Human; Immunoglobulin Domain; Immunoglobulins; In Vitro; Infection; Integral Membrane Protein; Kidney; Kidney Diseases; Kidney Failure; Maps; Mediating; Microfilaments; Microtubules; Mouse Strains; Mus; Mutate; Names; Neurons; Orthologous Gene; Pathogenesis; Pathologic; Pattern; Phenotype; Play; Predisposition; Protein Overexpression; Proteins; Range; Renal glomerular disease; Research Personnel; Resistance; Role; Scaffolding Protein; Specificity; Synapses; Transgenes; Transgenic Mice; Transgenic Organisms; Up-Regulation; alpha Actinin; domain mapping; extracellular; glomerular basement membrane; in vivo; migration; mouse model; neuronal guidance; podocyte; prevent; programs; renal epithelium

DESCRIPTION (provided by applicant): HIV-associated nephropathy (HIVAN) is a leading cause of renal failure in Blacks. The main pathologic feature of HIVAN is collapsing glomerulopathy, which is caused by the direct infection of podocytes by HIV-1. Infected podocytes show unique phenotypic changes including dedifferentiation, increased proliferation, and changes in the actin cytoskeleton. We have cloned a host gene named sidekick-1 (sdk-1), a transmembrane protein of the immunoglobulin superfamily, as being highly upregulated in HIV-1 transgenic podocytes, and we believe sdk-1 to have a key role in HIVAN pathogenesis. We have shown that sdk-1 is highly upregulated in glomeruli in both HIV-1 transgenic mice and in human kidney biopsies. Our data also show that sdk-1 and its ortholog sidekick-2 (sdk-2) function as homophilic adhesion molecules in cells such that each sidekick prefers to bind to its own kind, and we have begun to map the domains responsible. Moreover, sdk-1 and sdk-2 were shown by others to function as neuronal guidance molecules, targeting axons to specific synapses; this suggests that sdk-1 and sdk-2 may analogously have a critical role in determining and maintaining glomerular architecture normally and in disease. In this proposal: 1. We will determine: a) the critical domain(s) of sdk-1 and sdk-2 responsible for the specificity of sdk-1 and sdk-2's homophilic interactions; b) whether targeted disruption of this critical domain's function in HIV-1 podocytes in vitro and in vivo can prevent HIV-1 induced phenotypic changes. 2. We will identify phenotypic changes in podocytes induced by sdk-1 expression. We will determine: a) to what extent does targeted overexpression of sdk-1 in podocytes in transgenic mice recapitulate HIVAN pathophysiology; b) how overexpression of sdk-1 in podocytes effects their ability to interact with glomerular basement membrane components; c) if sdk-1 upregulation induced by HIV-1 infection changes podocye-podocyte adhesion in vitro? 3. We will characterize the interaction of sdk-1 with the actin cytoskeleton. We will identify:a) the potential intracellular sdk-1 interacting proteins including alpha actinin-4; b) the effects of sdk-1 expression on organization of actin filaments and microtubules in podocytes and on expression of other actin-associated molecules. 4. We will better characterize expression patterns of sdk-1 in normal kidney, HIVAN and other glomerular diseases and examine differences in sdk-1 and sdk-2 expression between HIVAN susceptible and HIVAN resistant mouse strains. These studies should elucidate the mechanisms by which sdk-1 contributes to podocyte dysfunction in HIVAN.

描述（由申请人提供）： 与HIV相关的肾病（Hivan）是黑人肾衰竭的主要原因。 Hivan的主要病理特征是肾小球病变，这是由HIV-1直接感染足细胞引起的。感染的足细胞显示出独特的表型变化，包括去分化，增殖增加以及肌动蛋白细胞骨架的变化。我们将一个名为SideKick-1（SDK-1）的宿主基因克隆，该基因是免疫球蛋白超家族的跨膜蛋白，因为在HIV-1转基因足细胞中被高度上调，并且我们认为SDK-1在HIVAN病原体中具有关键作用。我们已经表明，HIV-1转基因小鼠和人类肾脏活检中的肾小球中SDK-1高度上调。我们的数据还表明，SDK-1及其直系同源辅助-2（SDK-2）在细胞中充当均匀的粘附分子，因此每个辅助物都更喜欢与其自身的粘合物结合，我们已经开始绘制负责的域。此外，其他人证明了SDK-1和SDK-2充当神经元引导分子，将轴突靶向特定的突触。这表明SDK-1和SDK-2在确定和维持正常肾小球结构和疾病中可能具有关键作用。在此提案中： 1。我们将确定：a）负责SDK-1和SDK-2的临界域，负责SDK-1和SDK-2的同质相互作用的特异性； b）在体外和体内，该关键域在HIV-1足细胞中的靶向破坏是否可以防止HIV-1诱导的表型变化。 2。我们将确定由SDK-1表达诱导的足细胞的表型变化。我们将确定：a）转基因小鼠中SDK-1的靶向过度表达在多大程度上是对Hivan病理生理学的靶向过表达的； b）足细胞中SDK-1的过表达如何影响其与肾小球基底膜成分相互作用的能力； c）如果HIV-1感染诱导的SDK-1上调会改变体外足细胞粘附？ 3。我们将表征SDK-1与肌动蛋白细胞骨架的相互作用。我们将确定：a）包括α肌动蛋白4在内的潜在细胞内SDK-1相互作用蛋白； b）SDK-1表达对足细胞中肌动蛋白丝和微管的组织以及其他与肌动蛋白相关的分子的表达的影响。 4。我们将更好地表征正常肾脏，Hivan和其他肾小球疾病中SDK-1的表达模式，并检查Hivan易感性和抗Hivan抗小鼠菌株之间SDK-1和SDK-2表达的差异。 这些研究应阐明SDK-1在Hivan中导致足细胞功能障碍的机制。